The compound [1-(mercaptomethyl)cyclopropyl]acetic acid and its derivatives are important intermediates for the synthesis of leukotriene receptor antagonist that inhibits are the cysteiny leukotriene CysL T1 receptor. Leukotriene is associated with the inflammation and constriction of airway muscles and the accumulation of fluid in the lung. A number of leukotriene antagonists are described in EP 480,717 and EP 604,114, and U.S. Pat. No. 5,270,324. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.
Among the compounds disclosed in these patents are those which include a thiomethylcyclopropaneacetic acid moiety. This moiety is introduced using derivatives of [1-(mercaptomethyl)cyclopropyl]acetic acid. A number of methods for preparing [1-(mercaptomethyl)cyclopropyl]acetic acid are known, Most known syntheses for preparing [1-(mercaptomethyl)cyclopropyl]acetic acid use either thiolacetic acid or hydrogen sulfide derivatives to introduce the mercapto function. EP 480,717 discloses the [1-(mercaptomethyl)cyclopropyl]acetic acid is introduced using methyl [1-(mercaptomethyl)cyclopropyl]acetate, and the methyl [1-(mercaptomethyl) cyclopropyl]acetate is prepared from 1,1-cyclopropyldimethanol. An improved synthesis is used in U.S. Pat. No. 5,270,324 and EP 604,114, which involves first converting 1,1-cyclopropyldimethanol into the corresponding cyclic sulfite using thionyl chloride.
Subsequently, it has been discovered that [1-(mercaptomethyl)cyclopropyl]acetic acid can be prepared from [1-(acetylthiolmethyl)cyclopropyl]acetonitrile by conducting the basic hydrolysis in a biphasic system, the product may then be crystallized from a hydrocarbon such as hexane or heptane. In the previous process for preparing [1-(mercaptomethyl)cyclopropyl]acetic acid, the method for preparing cyclic sulfite results in a number of by-products thereby reducing the yield of the desired cyclic sulfite; the process also requires multiple aqueous extractions, and solvent switches rendering it difficult to adapt to large scale production. Alternative processes are disclosed in the literature (Bioorg Med Chem Lett., 5, 1995) and in WO 95/18107, WO 96/22987, and U.S. Pat. No. 5,523,477 and U.S. Pat. No. 5,534,651.
Due to the strong disagreeable odour used in prior art, the manipulation of these reagents and the corresponding synthetic intermediates is technically demanding. Further, essentially all the key intermediates in known syntheses are liquids or oils, which require either vacuum distillation or column chromatography for purification. In addition, the final step of each of known syntheses involves a hot basic hydrolysis in which the temperature ranges from 80° C. to aqueous reflux. Since [1-(mercaptomethyl)cyclopropyl]acetic acid is sensitive to oxidation, the use of such harsh reaction conditions leads to reduced yields and/or product of unacceptable purity. U.S. Pat. No. 6,512,140 disclosed a novel process for the preparation of [1-(mercaptomethyl)cyclopropyl]acetic acid which avoids the above-described disadvantages of known processes. However, it may have the corresponding disulfide of the final products, and the reaction temperature lower to 0° C. is inconvenient with respect to industrial application.